The present invention concerns an improved process for the production of tertiary amines by reductive amination. This improved process can be applied to the preparation of imidazole-containing benzodiazepines, which are inhibitors of farnesyl protein transferase that find utility in the treatment of a variety of cancers and other diseases (Ding, C. Z.; Hunt, J. T.; Kim, S. -h.; Mitt, T.; Bhide, R.; Leftheris, K. WO 9730992; Chem. Abstr. 1998, 127, 278213).
A number of methods have been previously reported for the reductive amination of carbonyl compounds with secondary amines in the presence of a reducing agent. The reducing agents previously used include: zinc (Lockemann, G. DE 503113; Chem. Abstr. 1931, 25, 522), H2/Pd(or Pt, Ni) (Emerson, W. S. Org. React. 1948, 4, 174; Schaus, J. M.; Huser, D. L.; Titus, R. D. Synth. Commun. 1990, 20, 3553), organoselenides, such as selenophenol (Fujimori, K.; Yoshimoto, H.; Oae, S. Tetrahedron Left. 1980, 21, 3385), NaBH4 (Verardo, G.; Giumanini, A. G.; Strazzolini, P. Synth. Commun. 1994, 24, 609), and NaCNBH3 (Lee, M.; Garbiras, B. J. Synth. Commun. 1994, 24, 3129). All these reducing agents are subject to one or more drawbacks. They are either toxic, or else they are not selective, with the result that a number of other reducible groups could be affected by side-reactions with these reagents. Reducing agents such as the organoselenides and NaCNBH3 are highly toxic, while zinc, NaBH4, and H2 over Pt, Pd, or Ni, for example, suffer from poor selectivity. NaBH(OAc)3 was subsequently introduced to address these problems (Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849) and this reagent was used in the preparation of the aforementioned imidazole-containing benzodiazepine compounds (Ding, C. Z.; Hunt, J. T.; Kim, S. -h.; Mitt, T.; Bhide, R.; Leftheris, K., WO 9730992; Chem. Abstr. 1998, 127, 278213). Although the desired products were obtained from 1 H-benzodiazepine starting materials, a large excess of aldehyde was required for a satisfactory conversion. In addition, expensive chromatographic separation of products was necessary, so that this method was not readily adaptable to large scale preparation.
Reduction of amines preformed from primary anilines and aldehydes to secondary amines with Et3SiH/TFA has been previously reported (Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633; Loim, N. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1968, 1345). Reduction of the preformed aminal from secondary amine and formaldehyde to give tertiary amine using Et3SiH/TFA has also been disclosed (Beulshausen, T.; Groth, U.; Schoellkopf, U. Liebigs Ann. Chem. 1992, 523).
The process for the production of tertiary amines by reductive alkylation of a secondary amine using hydrosilane and Lewis acid is the subject of U.S. Pat. No. 6,100,395, to Chen et al., which is commonly owned with the invention described herein. Optimization of the patented process entailed the use of an extended reaction period in order to improve the quality of the product. In practice, this led to a relatively long cycle time, on the order of 80-90 hours.